1-substituted 9beta, 10alpha-steroids of the androstane series



United States Patent 7 ABSTRACT OF THE DISCLOSURE This disclosure describes compounds of the class of 9/8,10a-steroids of the formula The compounds are pharmaceutically useful as hormonal or antihormonal agents.

The invention relates to novel 9fi,10a-steroids of the formula in which R is fluorine, chlorine, bromine, cyano, alkoxy, acyloxy, alkylthio, ar-alkylthio, acetylthio, propionylthio or oxo; R independently, is hydroxy, acyloxy, alkoxy, benzyloxy, cyclopenten-l-yloxy, 1-ethoxycyclopentyloxy or tetrahydropyranyloxy; R independently, is hydrogen, alkyl, alkenyl or alkynyl; R and R together are 0x0; and R (when R is a fluorine, chlorine, bromine, cyano,

3,409,642 Patented Nov. 5, 1968 2 alkoxy, acyloxy, alkylthio, acetylthio or propionylthio) is a 3-keto-A 3-keto-A 3-keto-A 3-keto-A or (when R is 0x0) a 3-keto-A 3-keto-A 3-acyloxy-A -or a 3-acyloxy-A -system.

An acyloxy group represented by the symbols R and R as well as a 3-acyloxy group, preferably contains the caproic acid, acid, succinic acid, malonic acid, benzoic acid.

An alkoxy or alkylthio group represented by the symbol R or an alkoxy group represented by the symbol R preferably contains 110 carbon atoms. Examples of such 1-5 carbon atoms. Examples of such groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, vinyl, allyl, 1'- and 2'-methallyl, ethynyl and propargyl. An ar-alkyl group is, for example, a phenyl-alkyl group where alkyl has the meaning given above. Such a group is, for example, benzyl.

Exemplary 9,3,10a-ster0ids of Formula I are:

lfl-acetylthio-l 7a-methyl-l 7,6-hydroxy-9fl, 1 ()u-androsta- 4,6-dien-3-one,

IB-acetylthio-l7a-methyl-17,6-acetoxy-9fl,lOa-androsta- 4,6-dien-3-one,

lfl-acetylthid17a-methyl-17 3-hydroxy-9fl, IOa-andmst- 4-en-3 -one,

lfl-propionylthio-l 7a-methyl-1 7fl-hydroxy-9fl, 10aandrosta-4,6-dien-3 -one,

1 3-acetylthio-17fi-hydroxy-9 8,10a-androsta-4,6-dien- 3-one,

1,8-propionylthio-17,8-hydroxy-9/5,10u-androsta-4,6-

dien-3-one,

lfl-ethylthio-l7a-methyl-17,6-hydroxy-9B, 1 Oa-androsta- 4,6-dien-3-one,

1/3-ethyIthio-l7a-methyl-l7fl-acetoxy 9fl, l Ou-andrOsta- 4,6-dien-3-one,

1,8-ethylthio- 1 Za-methyLI 7fl-hydroxy-9 3, 1 Oa-andrcst- 4-en-3-one,

lfl-methylthio-17a-methyl-l7p-hydroxy-9fl, 10u-androsta- 4,6 -dien-3-one,

1 3-benzylthio-1 7a-methyl-1 7 3-hydroxy-9y8, 1 Oa-andrcsta- 4,6-dien-3 -one,

lp-cyano-lh-methyl-l7 s-acetoxy-9 3,10a-androsta- 4, 6-dien-3-one,

LH-cyano-17a-methyl-17/3-acetoxy-9/i, IOu-androst- 4-en-3-one,

l-cyan0-17u-methyl-l 7,8-acetoxy-9/3, 1 OOz-androsta- 1,4,6-trien-3-one,

1 8, 1 7B-diacetoxy-9p, 10a-androsta-4,6-dien-3-one,

1 3, 1 7 3-d'iaeetoxy-17a-rnethyl-9 3, 10a-androsta-4,6-

dien-3-one,

lpgl 7,8-diacetoxy-1 7a-methyl-9p, 10a-andr0st-4-en- -one,

lfl-acetoxy-17a-methyl-17p-hydroxy-9fl,10a-androsta- 4,6-dien-3-one, 17 3-hydroxy-9fl,10a-androstaa4,6-diene-1,3-dione, 17a-methyl-17B-hydroxy-918,10a-androsta-4,6-diene- 1,3-dione, 1,17B-diacetoxy-9fl,10oc-androsta-1,4,6-trien-3-one, 1.5,17p3-diacetoxy-17a-methyl-9j8,l0a-androsta-4,6-dien 3-one, 1g-methoxy-l7i8-hydroxy-9 l3,10a-androsta-4,6-dien- 3-one,

ethoxy-17/3-hydroxy-9B,l0a-androsta-l,4,6-trien- 3-one, 1i-methoxy-17a-methyll7B-hydroxy-9fi,10a-androst- 4-en-3-one, lg-methoxy-17a-methyl-17B-hydroxy-9fi,10a-androsta- 4,6-dien-3-one, 1-methoxy-17 a-methyl- 17 B-hydroxy-9 {3,l0a-androsta- 1,4,6-trien-3-one, 1E,17fi-di-tetrahydropyranyloxy-l7u-methyl-9fi,10u-

androsta-4,6-dien-3-one, lE-chloro-l7fi-acetoxy-9fi,10a-androsta-4,6-dien-3-one, l-chloro-17fi-acetoxy-9fl,IOa-androsta-1,4,6-trien-3-one, lg-chloro-lh-methyl-l7fl-acetoxy-9B,10a-androsta-4,6-

d-ien-3-one, l-chloro-Hot-methyl-l7B-acetoxy-9p,l0a-androsta- 1,4,6-trien-3-one, 1E-bromo-17a-methyl-l7B-acetoxy-9B,lOu-androsta- 4,6-dien-3-one.

A preferred group of compounds of Formula I are those wherein R is fluorine, chlorine, bromine, alkoxy, acyloxy, alkylthio, ar-alkylthio, acetylthio, propionylthio or 0x0 and R, R and R have the meaning given above.

The novel 95,10a-steroids of Formula I can be obtained according to methods which are known per se from the chemistry of steroids of normal (i.e., 9u,10;3) configuration.

The introduction of a l-cyano group can, for example, be achieved by addition of hydrogen cyanide at the A- double bond of a 3-keto-A or 3-keto-A -9f3,10asteroid, especially one of the formula R2 H; I

in which R and R have the same meanings as above,

or a 6-dehydro-derivative thereof,

by means of alkali cyanides (such as potassium cyanide) in preferably polar organic solvents (such as alcohols, dioxan or dimethylformamide) at elevated temperature (e.g., reflux temperature) (see U.S. Patents Nos. 3,088,952 and 3,054,809). The l-cyano group can, moreover, be introduced with hydrogen cyanide formed in situ; for example, by treatment of the foregoing 95,10- steroids of Formula II with acetone cyanhydrin in the presence of a base (e.g., an alkali hydroxide vor carbonate) preferably with heating (e.g., at reflux temperature) (see Bull. Soc. Chim. France 1963, 2471).

By reaction of 3-keto-A or 3-keto-A -9fiJOasteroids, especially those of Formula II, with alkylmercaptans or ar-alkylmercaptans, there are obtained l-aralkyl or l-alkylthio-3-keto-A -9/3,wot-steroids or 6-dehydro-derivatives thereof; by reaction with thioacetic acid or thiopropionic acid, the corresponding l-acetylthio or 1-propionylthio compounds are obtained [see Chem. Ber. 96, 10 (1963); J. Org. Chem. 24, 277 (1959) and 27, 2693 (1962) as well as I. Am. Chem. Soc. 81, 1224 (1957)].

These reactions can be carried out using the mercaptan or the thioacid as a solvent or they can be carried out in the presence of other solvents (e.g., aromatic hydrocarbons such as benzene or ethers such as dioxan) at temperatures above or below room temperature, preferably between about 0 C. and about 80 C.-The reactions can if desired, be performed in the presence of a. catalyst (e.g., piperidine or hydrochloric acid).

For the preparation of 95,10u-steroids of Formula'l in which R represents an acyloxy, alkoxy, fluorine, chlorine or bromine, the l-hydroxy group of a l-hydroxy-3-keto- A -9B,10ocsteroid or -dehydro-derivative thereof is conveniently esterifled or etherified or, in free or esterified form, substituted by the named halogen atoms.

The esterification and the etherifi-cation of the l-hydroxy group can be effected according to methods known per se', for example, by treatment with an acylating agent (e.g., an acid anhydride such as acetic anhydride) in the presence of a base such as pyridine. The etherification can, for example, be effected with an alkyl halide such as methyl or ethyl iodide in the presence of a base such as methanolic caustic potash.

The substitution of a l-hydroxy or l-acyloxy group by a fluorine, chlorine or bromine atom can, for example, be effected by treating a correspondingly substituted 95,10asteroid, especially a 1-hydroxyor l-acyloxy-3-keto-A -9fi, l0a-steroid or 6-dehydro-derivative thereof, with hydrogen fluoride, chloride or bromide. This reaction is preferably undertaken at room temperature (e.g., 20-25 C.) in a non-ketonic, non-alcoholic, inert organic solvent (e.g., in aliphatic or aromatic hydrocarbons such as petroleum ether or benzene, toluene or xylene, or hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride or chlorobenzene, in nitrated hydrocarbon such as nitrobenzene or in ethers such as diethyl ether, dioxan or tetrahydrofuran).

The hydrogen fluoride, chloride or bromide is conveniently led as the dry gas into a solution of the l-hydroxyor l-acyloxy-3-keto-A -9fl,l0a-steroid or 6-dehydroderivative thereof in one of the named solvents, conveniently for a period of time from about /2 hour to about 10 hours. In doing this, the course of the reaction can be followed by thin layer chromatography or measurement of the UV- absorption spectrum of the reaction mixture.

A 1-hydroxy-9fi,10a-steroid can be prepared by reaction of a 3-hydroxy-A -9B,wot-steroid with N-brorno-succinimide in the presence of perchloric acid in tertbutanol and catalytic hydrogenation of the so-formed 3-keto-l-hydroxy-2-bromo-9B,IDOL-steroid intermediate or by addition of hypobromic acid at the A -double bond of a 3-keto- A -9fi,10a-steroid and subsequent catalytic hydrogenation of the so-formed bromohydrin intermediate, as above (see J. Chem. Soc., 1959, 4136).

A 1-halo-, especially a 1-chloro-3-keto-A -,A or A 9 9,l0a-steroid, can also-be prepared by reaction of a 1,3-diketo-9B,lOct-steroid, or 4-dehydro or 4,6-bisdehydroderivative thereof, with an acid halide, especially an acid chloride such as oxalyl chloride, sulphuryl chloride or phosphorus oxychloride.

A preferred method for the introduction of a l-acyloxy or l-alkoxy group or a l-fluorine, l-chlorine or l-brornine atom consists in splitting off the epoxide ring of a 1,2- epoxy-9B,10u-steroid, especially one of the formula III in which R2 and in halogenated described herembefore (i.e., the, oxidation of the 1,3-dihydroxy-A or A -grouping) is carried out with stronger oxidation agents (e.g., chromic acid in glacial acetic or in dimethylformamide), there are obtained l,3-diketo-A or A -9/3,l0a-steroids.

The manufacture of the 1,2-epoxy-steroids of Formula III or 6-dehydro-derivatives thereof is conveniently elfected by treatment of 9,3,la-steroids of Formula II or 6- dehydro-derivatives thereof with hydrogen peroxide in the presence of alkali (see U.S. application Serial No. 565,093 filed of even date herewith Compounds of Formula I in which R exhibits fi-configuration can be rearranged into the corresponding compounds in which R has tat-configuration by a reaction sequence of halogenation, 1,2-dehydrohalogentation and hydrogenation. Thus, for example, a 1 3-cyano-3-keto-95J0asteroid can be converted by treatment with bromine in glacial acetic into a 1Bcyano-2-bromo-3-keto 9 3,100:- steroid, the latter transformed with dehydrohalogenation agents (such as pyridine) into a 1-cyano-A -3-keto-9B,l0asteroid and this catalytically hydrogenated (e.g., with noble metals such as palladium) to a 1a-cyano-3-keto-9fi,l0usteroid.

In the compounds of Formula I obtained as described above, double bonds can be introduced, insofar as they are not already present, into the land/or 6-position. Compounds of Formula I in which R represents a 3-keto- A or A -system can be converted into 3-acyloxy-A or A -9fi,l0a-steroids.

For these reaction steps, the methods known from the chemistry of the normal steriods can be used.

The enol-esterification can,

genation.

The compounds of this invention of Formula I are pharmaceutically useful by such as tablets, drages, suppositories capsules or in conanabolic and antigonadotropic tain other therapeutically useful materials.

The following examples are illustrative but not limitative of this invention. All temperatures are stated in degrees centigrade.

Example 1 A solution of 0.5 g. of 17a-methyl-17 3-hydroxy-9fl, lOut-androsta1,4,6-trien-3-one in ml. of thioacetic acid Example 2 According to the process described in Example 1, from 17a-methyl-17B-acetoxy-9B,mot-androsta 1,4,6 trian 3- one there was obtained 15 -acetylthio 17a -methyl-l7fiacetoxy-9fi,10a-androsta-4,16-dien-3one. [a] 422 (dioxane). UV: 290 In/L/=23,800 m/L/=7,200. This compound is useful as an androgenic,

agent.

Example 3 A solution of 7.0 g. of 17a-methyl-l7,8-hydroxy-9/3, 10u-androsta-1,4,6-trien-3-one and 11 ml. of piperidine in ether)/ether (1:3) eluates yielded 1 3- ethylthio-17a-methyl-17,3-hydroxy 9 3,100 androsta-4, 6-dien-3-one, melting point: l26127 (recrystallized from ether). [a] =495 (dioxane). UV: kmax. 284 m/L/=21,400. This compound is useful as an anabolic and antigonadotropic agent.

Example 4 methyl 17 8 acetoxy-9 3,10a- Melting point 245-247 [from acetone/(isopropyl ether)] [a] =518 (dioxane). UV: Amax. 286 ITl/L/=24,350.

Example 6 A solution of 0.5 g. of 119,2/9-epoxy-l7a-methyl-l7fihydroxy-9p,10a-androsta-4,6-dien-3-one in ml. of absolute ether was added to a solution of 0.5 g. of lithium aluminum hydride in 20 ml. of absolute ether. The mixture was stirred for 1 hour at room temperature, then carefully treated with 2 ml. of saturated sodium sulfate solution. The resultant granular precipitate was filtered off and the filtrate evaporated to dryness. The so-obtained crude 1;3,3,17B trihydroxy-17a-methyl-9B,lOa-androsta- 4,6-diene was dissolved in 50 ml. of chloroform and treated with 3.0 g. of manganese dioxide. The mixture was stirred at room temperature for 1 hour. The manganese dioxide was then filtered off and the filtrate evaporated to dryness. There was thus obtained 0.5 g. of crystals which were twice recrystallized from ether yielding pure 15,1713-dihydroxy 17a. methyl-9,8,10u-androsta-4,6-dien- 3-one, melting point 196-197". UV: xmax. 288

The above-utilized starting material can be prepared as follows:

A solution of 1.0 g. of 17oc-methyl-17,8-hydroxy-9;8,10uandrosta-1,4,6-trien-3-one in 20 ml. of methanol was treated at with 1 ml. of caustic soda and 2 ml. of 30% hydrogen peroxide and then maintained at 0 for 3 hours. The mixture was then neutralized with acetic acid, poured on ice water and extracted with methylene chloride. The methylene chloride extracts (washed neutral with water) were dried with sodium sulfate and the solvent evaporated in vacuo. The resultant residue was then chromatographed on silica gel. The ether/ petroleum ether (1: 1) eluates, pure according to thin layer chromatogram, were combined and recrystallized from methylene chloride/isopropyl ether yielding 1/3,2fi-epoxy-l7a-methyl-17,8- hydroxy-9fl,10a-androsta-4,6-diene 3 one, melting point 160. [a] -==-760. UV: Amax. 293 m /e=20,000.

Example 7 2.0 ml. of acetyl chloride in 25 ml. of dry benzene was added within 10 minutes to a solution of 2.0 g. of 1 3,175- dihydroxy-17a-methyl-9l3,10a-androsta-4,6-dien-3-one in 50 ml. of dry pyridine at 0 C. The reaction mixture was stirred for 2 hours at 0 C. and then for hours at 20 C., poured into a mixture of ice and diluted hydrochloric acid and extracted with methylene chloride. The extract was Washed with water until neutral, dried and evaporated in vacuo. The residue was chromatographed on a 50 fold amount of silica gel using ethyl acetate petroleum ether (3:1) as the eluting agent. The first fractions afiorded pure, amorphous 15,17fl-diacetoxy 17 a methyl-913,10 androsta-4,6-dien-3-one, [a] =427 (in dioxan); the following fractions gave pure, amorphous 1,8-acetoxy-17 0:.- methyl 175 hydroxy 93,100: androsta-4,6-dien-3-one, [a] =-513 (in dioxan). This compound is useful as an anabolic and antigonadotropic agent.

Example 8 A mixture of 4.0 g. of 17 e-methy1-17 p-hydroxy-9p,10uandrosta-l,4,6-trien-3-one and 80 ml. of thiopropionic acid was kept for 10 minutes at 25 C. The reaction mixture was processed as described in Example 1 and chromatographed on silica gel. The ether-petroleum ether (2: 1) fractions afforded pure, amorphous 1B-propionylthio-17amethyl 17p hydroxy 913,10); androsta-4,6-dien-3-one, [a] =-469 (in dioxan) UV: )imax. 230 m /e=7400, 292 m /e=2-2,700. This compound is useful as an androgenic, anabolic and antigonadotropic agent.

Example 9 0.5 g. of 17a-methyl-l7fl-hydroxy-9fl,19a-androsta-1,4,6- trien-3-one was dissolved in 5 ml. of methyl mercaptan at 20 C. The solution was kept for 2 hours at 20 C. and then concentrated in vacuo. The residue was chromatographed on 20 g. of silica gel. Elution with ether gave pure 1fl-methylthio-17a-methyl-175-hydroxy-9B,10aandrosta-4,6-dien-3-one, melting point 164-166 (from methylene chloride-isopropyl ether); [u] ='4-57; UV: Arnax. 284.5 m l/5.120900. This compound is useful as an androgenic, anabolic and antigonadotropic agent.

Example 10 A mixture of 2.5 g. of 17a-methy1-17 {3-hydroxy-913J0aandrosta-l,4,6-trien-3-one, 35 ml. of isopropyl mercaptan and 4 ml. of piperidine was refluxed from 70 minutes. The excess of isopropyl mercaptan was evaporated in vacuo and the residue was chromatographed ether-petroleum ether (1:1) eluates afforded pure 1B-isopropylthio 17a methyl 175 hydroxy-9p,10a-androstaandrosta-4,6-dien-3-one, melting point 164-166 (from methylene chloride-isopropyl ether); [a] =457; UV; kmax. 284.5 ma/e=20,000. This compound is useful as an androgenic, anabolic and antigonadotropic agent.

Example 11 A mixture of 4.0 g. of 17a-methyl-17 8-hydroxy-9B,10aandrosta-l,4,6- trien-3-one, 4 ml. of pyridine, 400 ml. of benzene and 8 ml. of benzyl mercaptan was kept for 15 minutes at 25 C. After the usual work-up there was obtained 1B-benzylthio-17u-methyl-17fl-hydroxy-9B,lOu-androsta-4,6-dien-3-one, melting point 88-90 (from ether). [a] =433, UV; xmax. 283 mu/e=20,500. This compound is useful as an androgenic, anabolic and antigonadotropic agent.

Example 12 Tablets of the following formulations were prepared:

Mg. lfl-acetylthio 17a methyl-17,B-hydroxy-9,B,10a-

androsta-4,6-dien-3-one Lactose Corn starch 72.5 Talc 1.35 Magnesium stearate 0.15 150.00

lfl-acetylthio 17cc methyl-17,8-acetoxy-9fi,10a-

androsta-4,6-dien-3-one Lactose 75 Corn starch 72.5 Talc 1.35 Magnesium stearate 0.15 150.00

What is claimed is: 1. A compound of the formula Ra (EH3 L R3 a a E i H /i H in which R is fluorine, chlorine, bromine, cyano, alkoxy having up to 10 carbon atoms, acyloxy having up to 20 carbon atoms, alkylthio having up to 10 carbon atoms, phenyl-alkylthio wherein the alkyl moiety has up to 10 carbon atoms, acetylthio, propionylthio or oxo; R independently, is a hydroxy, acyloxy having up to 20 carbon atoms, alkoxy having up to 10 carbon atoms, benzyloxy, cyclopenten-l-yloxy, 1-ethoxycyclopenty1oxy or tetrahydropyranyloxy; R independently, is hydrogen, alkyl having up to 5 carbon atoms, alkenyl having up to 5 carbon atoms or alkynyl having up to 5 carbon atoms; R and R together are oxo; and R (when R is fluorine, chlorine, bromine, cyano, alkoxy, having up to 10 carbon atoms, acyloxy having up to 20 carbon acetylthio or propionylthio) is a atoms, alkylthio,

3 -keto-A 3-keto-A 3-keto-A 3-keto-A 3-acyloXy-A or a 3-acyl'oxy-A -system or (when R is oxo) a 8. A compound as in claim 1 which is lp-acetoxy-lhmethyl-17/3-hydroXy-9BJ 0a-androsta-4,6-dlen-3-one.

9. A compound as in claim 1 which is l/i-propionylthio-l7a-methyl-l7fl-hydroxy-9fi,10a-androsta-4,6-dien-3- one.

10. A compound as in claim 1 which is lfl-methylthio- 17a-methyl-17,6-hydroxy-9,8,10iz-androsta-4,6-dien-3-one.

11. A compound as in claim 1 which is 1,8-isopropylthio 17a-methyl 17,8-hydroxy 9,8,10a-andr0sta 4,6- dien-3-one.

12. A compound as in claim 1 which is Ifi-benzylthio- 17a-methyl-17B-hydroxy-9B,10a-androsta-4, 6-dien-3-one.

13. A compound as in claim 1 wherein R is alkyl having up to 5 carbon atoms.

14. A compound as in claim having up to 5 carbon atoms.

15. A compound as in claim 1 having up to 5 carbon atoms.

16. A compound as in claim 1 wherein R has a B sterec-configuration.

1 wherein R is alkenyl wherein R is alkynyl References Cited UNITED STATES PATENTS 2,875,215 2/1959 Dodson 3,198,792 8/1965 Reerink et al LEWIS GOTTS, Primary Examiner. E. G. LOVE, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,409,642 November 5, 1968 Andor Furst et a1.

It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:

Column 5, line 25, "dehydrohalogentation" should read dehydrohalogenation line 64, "in organic" should read inorganic Column 6, line 29, "mu/c=23,800, 28" should read mn/e=23,800, 228 Column 7, line 67, "98,19d" should read 98,1001 Column 8, line 7, "from" should read for line 11, cancel "androsta", second occurrence; lines 11 to 13, "l64-l66 (from methylene-chlorideisopropyl ether;) [a] Z5= 457; UV; Amax. 284.5 mu/e=Z0,000" should read 112ll4 (from ether-isopropyl ether) [u] 25=-489; UV: Amax. 284 mu/e= 21,000 line 24, "UV;" should read UV: Column 9, line 28, "196,10u" should read 96,1001

Signed and sealed this 7th day of April 1970.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR. Attesting Officer Commissioner of Patents 

